The Role Of Thioredoxin-1 Suppressing Depressive Behavior Induced By Methamphetamine

Methamphetamine is commonly named as "ice", the pure appearance is white crystal clear, which is stimulant on central nervous system. The long-term use of METH can produce drug dependence. Once methamphetamine addiction is induced, its withdrawal is very difficult, and anxiety, depression, psychomotor retardation and other symptoms are induced during the withdrawal period, which seriously affect the physical health and mental health problems of patients. The mechanism on methamphetamine addiction is unclear, thus studies on the mechanism of methamphetamine addiction has been the hotspot of biomedical field.Methamphetamine addiction causes oxidative stress, and redox equilibrium disorder, and then induces injury. Thioredoxin-1 (Trx-1) is existed extensively in the body, which is a protein of low molecular weight, and an important redox regulating protein to maintain the homeostasis. Trx-1 has roles in promoting cell proliferation, regulating activity of transcriptional factor and inhibiting apoptosis. Trx is divided into three types, Trx-1, Trx-2 and another Trx specific protein in sperm cells, Trx-3.These different types of Trx have different function. Trx-1 is the most common type and widely distributed. Trx and Thioredoxin reductase (TrxR) NADPH together constitute the Trx reducing system.The depressive disorders are related with monoamine, neurotransmitter receptors, neurotrophic factors, oxidative stress, cytokines, NO signaling pathway and neurodegeneration. The depressive disorder related brain areas are the hippocampus and prefrontal cortex (PFC). The addiction induced by METH was examined by conditioned place preference, (CPP) model. The depressive behabiour was detected by using tail suspension assay after the natural withdrawal a week. The time difference of "non-state" was compared between the group of wild type mice and the group of Trx-1 overexpression transgenic mice. Our results showed that the depressive behavior was induced after METH withdrawal, however, depressive behavior was suppressed in Trx-1 overexpression mice.Then we examined the expressions of Trx-1, cAMP response element binding protein(CREB), cyclin-dependent kinase 5(CDK5), monoamine oxidase(MAO),5-serotonin transporter(ST), NR2B, the subunit of N-methyl-D-aspartate(NMD A) glutamate receptor 1(GluR1) and Ca2+/calmodulin-dependent protein kinase(CaMKII) in hippocampus and PFC. We found that METH induced the level changes of Trx-l, CREB and CDK5, which were blocked in Trx-1 overexpression mice. As well as exprssions of MAO and ST were induced by METH withdrawal, the decreases of NR2B, GluRl, p-CaMKII were induced too, whereas these changes were recovered in Trx-1 overexpression mice.In conclusion, Trx-1 overexpression suppresses depressive behavior induced by METH by restoring pathways on DA,5-HT, glutamate. Thus, Trx-1 may be a new target for treatment on depressive behavior induced by METH withdrawal.